The present invention relates to di-N-substituted piperazines and 1,4-di-substituted piperidines useful in the treatment of cognitive disorders, pharmaceutical compositions containing the compounds, methods of treatment using the compounds, and to the use of said compounds in combination with acetylcholinesterase inhibitors.
Alzheimer""s disease and other cognitive disorders have received much attention lately, yet treatments for these diseases have not been very successful. According to Melchiorre et al. (J. Med. Chem. (1993), 36, 3734-3737), compounds that selectively antagonize M2 muscarinic receptors, especially in relation to M1 muscarinic receptors, should possess activity against cognitive disorders. Baumgold et al. (Eur. J. of Pharmacol., 251, (1994) 315-317) disclose 3-xcex1-chloroimperialine as a highly selective m2 muscarinic antagonist.
The present invention is predicated on the discovery of a class of di-N-substituted piperazines and 1,4-di-substituted piperidines, some of which have m2 selectivity even higher than that of 3-xcex1-chloroimperialine. Logemann et al (Brit. J. Pharmacol. (1961), 17, 286-296) describe certain di-N-substituted piperazines, but these are different from the inventive compounds of the present invention. Furthermore, the compounds of Logemann et al. are not disclosed to have activity against cognitive disorders.
The present invention relates to compounds according to the structural formula 1, 
including all isomers and pharmaceutically acceptable salts, esters, and solvates thereof,
wherein
one of Y and Z is N and the other is N, CH, or C-alkyl;
X is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94NR6xe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94CH2xe2x80x94, xe2x80x94CSxe2x80x94, xe2x80x94C(OR5)2xe2x80x94, xe2x80x94C(SR5)2xe2x80x94, xe2x80x94CONR20xe2x80x94, xe2x80x94C(alkyl)2xe2x80x94, xe2x80x94C(H)(alkyl)xe2x80x94, xe2x80x94NR20xe2x80x94SO2xe2x80x94, xe2x80x94NR20COxe2x80x94, 
xe2x80x83(wherein X1 is xe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94, or xe2x80x94NR7xe2x80x94), 
xe2x80x83hydrogen, acyl, alkyl, alkenyl, cycloalkyl, cycloalkyl substituted with up to two alkyl groups, cycloalkenyl, bicycloalkyl, arylalkenyl, benzyl, benzyl substituted with up to three independently selected R3 groups, cycloalkylalkyl, polyhaloacyl, benzyloxyalkyl, hydroxyC2-C20alkyl, alkenylcarbonyl, alkylarylsulfonyl, alkoxycarbonylaminoacyl, alkylsulfonyl, or arylsulfonyl, additionally, when X is xe2x80x94CH2xe2x80x94, R may also be xe2x80x94OH; in further addition, when X is not N, R may also be hydroxymethyl, in further addition, R and X may combine to form the group Prot-(NOAA)rxe2x80x94NHxe2x80x94 wherein r is an integer of 1 to 4, Prot is a nitrogen protecting group and when r is 1, NOAA is a naturally occuring amino acid or an enantiomer thereof, or when r is 2 to 4, each NOAA is a peptide of an independently selected naturally occuring amino acid or an enantiomer thereof;
R1 and R21 are independently selected from the group consisting of alkyl, alkenyl, cycloalkyl, cycloalkenyl, bicycloalkyl, alkynyl, cyano, aminoalkyl, alkoxycarbonyl, aminocarbonyl, hydroxyguanidino, alkoxycarbonylalkyl, phenyl alkyl, alkylcarbonlyoxyalkyl, 
xe2x80x83H, xe2x80x94OH, (provided R1 and R21 are both not xe2x80x94OH and Y is not N), formyl, xe2x80x94CO alkyl, xe2x80x94COacyl, xe2x80x94COaryl, and hydroxyalkyl; additionally R1 and R21 together may form the group 
xe2x80x83in further addition, R1 and R21 together with the carbon atom to which they are attached may form the group 
xe2x80x83or R1 and R21 together with the carbon atom to which they are attached may form a saturated heterocyclic ring containing 3 to 7 carbon atoms and one group selected from S, O, and NH;
R2 is H, alkyl, alkenyl, cycloalkyl, cycloalkyl substituted with 1 to 3 independently selected R3 groups, cycloalkenyl, hydroxyC2-C20alkyl, alkynyl, alkylamide, cycloalkylalkyl, hydroxyarylalkyl, bicycloalkyl, alkynyl, acylaminoalkyl, arylalkyl, hydroxyalkoxyalkyl, azabicyclo, alkylcarbonyl, alkoxyalkyl, aminocarbonylalkyl, alkoxycarbonylaminoalkyl, alkoxycarbonylamino(alkyl)alkyl; alkylcarbonyloxyalkyl, arylhydroxyalkyl, alkylcarbonylamino(alkyl)alkyl, dialkylamino, 
xe2x80x83(wherein q is an integer of 0 to 2) 
xe2x80x83wherein n is 1-3 
xe2x80x83wherein m is an integer of 4 to 7, 
xe2x80x83wherein t is an integer of 3 to 5, 
xe2x80x83(wherein R29 is H, alkyl, acyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylsulfonyl, arylsulfonyl), 
xe2x80x83(wherein Q is O, NOH, or NO-alkyl), or when Z is xe2x80x94CHxe2x80x94, R2 may also be alkoxycarbonyl, hydroxymethyl, xe2x80x94N(R8)2;
R3, R4, R22, R24, and R25 are independently selected from the group consisting of H, halo, alkoxy, benzyloxy, benzyloxy substituted by nitro or aminoalkyl, haloalkyl, polyhaloalkyl, nitro, cyano, sulfonyl, hydroxy, amino, alkylamino, formyl, alkylthio, polyhaloalkoxy, acyloxy, trialkylsilyl, alkylsulfonyl, arylsulfonyl, acyl, alkoxycarbonyl alkylsulfinyl; xe2x80x94OCONH2, xe2x80x94OCONH-alkyl, xe2x80x94OCON(alkyl)2, xe2x80x94NHCOO-alkyl, xe2x80x94NHCO-alkyl, phenyl, hydroxyalkyl, or morpholino;
each R5 and R6 is independently selected from the group consisting of H and alkyl, provided that when X is C(OR5)2 or C(SR5)2, both R5 groups cannot be H, and in addition, when X is C(OR5)2 or C(SR5)2, the two R5 groups in X may be joined to form xe2x80x94(CH2)pxe2x80x94 wherein p is an integer of 2 to 4:
R7 is independently selected from the group consisting of H, alkyl, arylalkyl, cycloalkyl, aryl and aryl substituted with R3 and R4 as defined herein;
each R8 is independently selected from the group consisting of H, hydroxyalkyl, or alkyl or two R8 groups may be joined to form an alkylene group;
R9 is H, alkyl, or acyl:
R20 is H, phenyl or alkyl; and
R27 and R28 are independently selected from the group consisting of H, alkyl, hydroxyalkyl, arylalkyl, aminoalkyl, haloalkyl, thioalkyl, alkylthioalkyl, carboxyalkyl, imidazolyalkyl, and indolyalkyl, additionally R27 and R28 may combine to form an alkylene group.
In a preferred group of compounds Y and Z are N
In another preferred group of compounds Y is CH and Z is N
In another preferred group of compounds R is 
In another preferred group of compounds R3 and R4 are H and either R1 is cycloalkyl, alkyl, or CN and R21 is H or R1 and R21 together form xe2x95x90CH2 or xe2x95x90O.
In another preferred group of compounds R is 
X is O, SO or SO2, R3 and R4 are H and either R1 is cycloalkyl, alkyl, or CN and R21 is H or R1 and R21 together form xe2x95x90CH2 or xe2x95x90O.
In another preferred group of compounds Y and Z are N, R1 is cycloalkyl, alkyl or CN, R21 is H and R2 is cycloalkyl or 
In another preferred group of compounds Y is CH, Z is N, and R2 is cycloalkyl or 
In another preferred group of compounds at least one of R27 and R28 is alkyl.
In another preferred group of compound one of R27 or R28 is methyl and the other is hydrogen.
In another preferred group of compounds R is 
Another preferred group of compounds is the group represented by the formula 
wherein R, X, R1, R27, and R21 are as defined in the following table
or having the structural formula 
Another group of preferred compounds of formula I are:
(in the table that follows, when R2 is substituted cyclohexyl, the substituent positions are numbered as follows: 
Another aspect of the invention is a pharmaceutical composition which comprises a compound having structural formula I as defined above in combination with a pharmaceutically acceptable carrier.
Another aspect of the invention is the use of a compound formula I for the preparation of a pharmaceutical composition useful in the treatment of cognitive disorders and neurodegenerative diseases such as Alzheimer""s disease.
Yet another aspect of the invention comprises a method for making a pharmaceutical composition comprising mixing a compound of formula I with a pharmaceutically acceptable carrier.
Another aspect of this invention is a method for treating a cognitive or neurodegenerative disease comprising administering to a patient suffering from said disease an effective amount of a compound of formula I.
Another aspect of this invention is a method for treating cognitive and neurodegenerative diseases, such as Alzheimer""s disease with a compound of formula I in combination with an acetylcholinesterase inhibitor.
Another aspect of this invention is a method for treating a cognitive or neurodegenerative disease comprising administering to a patient suffering from said disease an effective amount of a combination of a compound capable of enhancing acetylcholine release (preferably an m2 or m4 selective muscarinic antagonist) with an acetycholinesterase inhibitor.
Another aspect of this invention is a kit comprising in separate containers in a single package pharmaceutical compounds for use in combination to treat cognitive disorders in one container a compound of formula I or a compound capable of enhancing acetylcholine release (preferably an m2 or m4 selective muscarinic antagonist) in a pharmaceutically acceptable carrier and in a second container an acetylcholinesterase inhibitor in a pharmaceutically acceptable carrier, the combined quantities being an effective amount.